The US is currently experiencing a serious epidemic of methamphetamine (Meth) use as a recreational drug and as of July 2005, Meth use has surpassed cocaine use as a street or club drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. Blood monocyte derived dendritic cells (DC) are the first line of defense against HIV-1 infection and are the initial target of HIV-1 in injection drug users. Although evidence of immune dysfunctions has been reported in Meth users, the molecular basis of the immunopathogenesis of HIV-1 infection in Meth users has not been delineated. Further, the effects of Meth abuse on the activities of DC that lead to HIV-1 disease progression in the Meth using population has not been examined. The current application focuses on novel, DC based immunotherapeutic and/or translational research strategies against susceptibility to and progression of HIV-1 infections in Meth using populations. Consequently, the following hypothesis will be tested by the proposed experiments: Meth is a co-factor in the pathogenesis of HIV-1 infections by acting in synergy with certain HIV-1 proteins on DC functions subsequently leading to dysregulation of the immune system of the infected host. Further, we propose that Meth mediates these effects on DC through several mechanisms including: 1) down regulating the expression of various costimulatory molecules, chemokines (that are necessary for DC maturation, effective antigen presentation, cell migration, and T cell proliferation), and a reciprocal upregulation of HIV-1 entry coreceptors (CCR5 and CXCR4) that are known to facilitate HIV-1 infection;2) upregulating indolamine 2,3 dioxygenase (IDO) that suppresses T cell immune functions;and 3) upregulating the DC-specific, CD4 independent virus attachment receptor, DC-SIGN, present on DC. Further, we shall determine the mechanism(s) of Meth mediated dysregulation of DC functions by examining signal transduction pathways and using Meth specific siRNA and receptor inhibitors. Our preliminary studies show that Meth significantly downregulates the expression of costimulatory molecules and HIV-1 suppressing (3-chemokines with a reciprocal upregulation of HIV-1 coreceptors, DC-SIGN and IDO, and these effects appear to be mediated via dysregulation of mitogen-activated protein (MAP) kinases. Resultant data will be stratified on the basis of HIV-1 disease status, CD4 counts, HIV-1 viral load and Meth use. These studies may lead to novel anti-HIV-1 therapeutic or translational research strategies such as targeting the CD4 independent virus attachment receptor, DCSIGN, or devising inhibitors of IDO, DC-SIGN, CCR5/CXCR4 and specific dopamine receptors or stimulating the expression of costimulatory-and (3-chemokine molecules in high risk Meth using and non using HIV-1 infected subjects.